PTAB

IPR2023-00050

TWi PharmaceuTicals Inc v. Merck Serono SA

Title: Cladribine Regimen for Treating Multiple Sclerosis
Brief Description: The ’903 patent claims a method for treating relapsing-remitting or early secondary progressive multiple sclerosis (MS) by orally administering cladribine. The method involves a specific sequence of an induction period, a cladribine-free period, a maintenance period, and a subsequent cladribine-free period, with defined total dosages for the treatment periods.

Prior Art Relied Upon: Bodor (Patent 7,888,328), which is noted as having the same disclosure as Bodor (WO 2004/087101).
Core Argument:
- Prior Art Mapping: Petitioner argued that Bodor discloses every limitation of the challenged claims. Bodor teaches an oral cladribine treatment for MS comprising two months of administration (5-7 days of 10 mg tablets each month) followed by "ten months of no treatment." Petitioner asserted a person of ordinary skill in the art (POSITA) would infer this 12-month cycle is repeated, with the second treatment round constituting the claimed "maintenance period." The petition contended that both the induction and inferred maintenance periods would use the same dosage, as was standard practice. For a patient of average weight (e.g., 70 kg), Bodor's dosing regimen (120 mg total over two months) calculates to 1.71 mg/kg, anticipating the claimed total dose of "about 1.7 mg/kg." The 10-month "no treatment" period in Bodor was argued to meet the claimed "cladribine-free period" of about 8-10 months.
- Key Aspects: The core of the anticipation argument relied on the inference that Bodor’s finite "ten months of no treatment" implies a subsequent, repeated treatment cycle, an interpretation Petitioner noted was adopted by the Examiner during prosecution.

Prior Art Relied Upon: Bodor (Patent 7,888,328) and the common knowledge of a POSITA.
Core Argument:
- Prior Art Mapping: This ground serves as an alternative to anticipation. If repetition of the treatment cycle is not considered inherent in Bodor, Petitioner argued it would have been obvious to a POSITA to repeat the cycle. Bodor provided the initial 2-month induction period, the dosage, and the 10-month drug-free interval.
- Motivation to Combine (with common knowledge): A POSITA would repeat Bodor's treatment method because it was well-known that immunotherapies for chronic conditions like MS often required multiple rounds to be effective. The nature of MS, with its relapsing symptoms, would motivate clinicians to re-administer a partially successful treatment.
- Expectation of Success: A POSITA would have an expectation of success because repeating treatment cycles was the standard medical approach for immunosuppressants. Other successful MS therapies, such as mitoxantrone, followed a similar cyclical administration pattern.

Prior Art Relied Upon: Bodor (Patent 7,888,328) and Rice (a 2000 article in Neurology).
Core Argument:
- Prior Art Mapping: This ground reinforces the argument for repeating the treatment cycle. Bodor taught the oral formulation and initial dosing schedule, while Rice provided an explicit rationale for repeating cladribine therapy. Rice disclosed that MS patients were "retreated" during a long-term follow-up phase after an initial treatment course.
- Motivation to Combine: A POSITA would combine Bodor’s oral formulation with Rice’s explicit teaching of retreatment to create an effective, long-term oral therapy. Rice’s promising results showing a "trend toward a beneficial cladribine effect" with repeated dosing would motivate a POSITA to apply this principle to Bodor’s method. Furthermore, Rice's subcutaneous dose of 0.7 mg/kg, when adjusted for the ~42% oral bioavailability disclosed in Bodor, calculates to ~1.67 mg/kg, providing a strong motivation to arrive at the claimed oral dose.
- Expectation of Success: The positive results in Rice, which showed that retreatment was beneficial and that cladribine "virtually eliminated" gadolinium-enhancing lesions, provided a strong expectation of success.

Scope of Claim 17 vs. Claim 1: A central contention was that the Examiner erred during prosecution by misapprehending the scope of challenged claim 17. Petitioner argued that claim 17, which recites an induction dose of "about 1.7 mg/kg to about 3.5 mg/kg" and a maintenance dose of "about 1.7 mg/kg," explicitly covers an embodiment where the induction and maintenance doses are equal (1.7 mg/kg). This was contrasted with un-challenged claim 1, which required the maintenance dose to be lower than the induction dose. Petitioner asserted the Examiner improperly analyzed claim 17 as if it also contained this "lower than" limitation, leading to its erroneous allowance.

Against §325(d) Denial (Same Art/Arguments): Petitioner acknowledged that Bodor was before the Examiner but argued for institution based on material Office error. The petition asserted that the Examiner misconstrued the scope of claim 17, as described above. Because the Examiner understood Bodor to teach an "equal dosage" regimen but believed claim 17 required a "lower" dosage regimen, the Examiner allowed the claim. Petitioner contended that had the Examiner correctly understood that claim 17 covers the very "equal dosage" embodiment taught by Bodor, the claim would have been rejected.
Against §314(a) Denial (Fintiv Factors): Petitioner argued that discretionary denial based on a parallel litigation (*Merck KGaA et al v. Accord Healthcare, Inc.*) was inappropriate. The key reasons asserted were that the litigation was in its preliminary stages with no trial date set, minimal investment had been made by the parties, and Petitioner was not a party to that litigation. Therefore, the factors weighed strongly against exercising discretion to deny institution.

Petitioner requested institution of an inter partes review and a final written decision cancelling claims 17, 19-20, and 22-29 of the ’903 patent as unpatentable.